Down syndrome (DS) is a complex developmental disorder with diverse pathologies that affect multiple tissues and organ systems. Clear mechanistic description of how trisomy of chromosome 21 gives rise to most DS pathologies is currently lacking and is limited to a few examples of dosage-sensitive trisomic genes with large phenotypic effects. The recent advent of cellular reprogramming technology offers a promising way forward, by allowing derivation of patient-derived human cell types in vitro. We present general strategies that integrate genomics technologies and induced pluripotent stem cells to identify molecular networks driving different aspects of DS pathogenesis and describe experimental approaches to validate the causal requirement of candidate network defects for particular cellular phenotypes. This overall approach should be applicable to many poorly understood complex human genetic diseases, whose pathogenic mechanisms might involve the combined effects of many genes.